The idiopathic interstitial pneumonias (IIP) represent a group of acute and chronic diffuse parenchymal lung diseases of unknown etiology. Idiopathic pulmonary fibrosis (IPF) is the most deadly and common type of IIP. As our understanding IPF evolves, it is evident that IPF is a heterogeneous disease. We previously demonstrated that multiple histopathologic patterns of IIP often exist within the same patient. Similarly, the same patient may exhibit areas of both inflammation and fibrosis, depending on the area of lung examined. There is no cure for IPF. The current recommended treatment regimen is anti-inflammatory and combines a cytotoxic agent (such as azathioprine or cyclophosphamide) with prednisone (American Thoracic Society, 2000). Although some patients seem to respond or stabilize, there are few rigorous data clearly elucidating the efficacy and safety of this regimen for patients diagnosed with IPF using current diagnostic guidelines. It is plausible that the failure of current therapeutic approaches reflects the lack of a simultaneous, multi-faceted assault against multiple biologically plausible targets involved in the pathogenesis of IPF. We hypothesize that novel therapies engineered to exploit specific pathophysiologic features of IPF will prove to have the greatest therapeutic success. With these concepts in mind, we propose two novel therapeutic trials for previously untreated patients with IPF. IPF is characterized by the overproduction of pro-fibrotic leukotrienes and underproduction of anti-inflammatory PGE2. Our first protocol compares the combination of two agents selected to correct this imbalance: zileuton plus N-acetyl cysteine versus standard therapy with azathioprine plus prednisone. IPF is also characterized by increased expression of the profibrotic cytokine IL-13 receptor compared to other types of IIP. Our second protocol advantages this observation by utilizing an aerosolized fusion protein comprised of human IL-13 and a mutated form of Pseudomonas exotoxin. Internalization of this fusion protein results in cellular apoptosis. Both trials are randomized, double-blind, placebo-controlled trials. The primary endpoint in each trial is a combination of death or decline in FVC of >10%. Secondary endpoints include safety, changes in pulmonary function, quality of life, dyspnea, six-minute walk distance, change in saturation during a six-minute walk test, and respiratory hospitalizations. These protocols will define the role of standard therapy, test the efficacy of targeted combination therapy, and explore the promise of a novel approach to the design and delivery of therapeutic agents for IPF. (End of Abstract)